Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes

Abstract

2-Chlorodeoxyadenosine (CdA), an adenosine-deaminase-resistant purine deoxynucleoside, is markedly toxic toward human T-lymphoblastoid cell lines in vitro and is an effective agent against L1210 leukemia in vivo. The present studies have examined the toxicity, and in some cases, metabolism, of CdA in (1) multiple established human cell lines of varying phenotype, (2) leukemia and lymphoma cells taken directly from patients, (3) normal bone marrow cells, and (4) normal peripheral blood lymphocytes. Nanomolar concentrations of CdA blocked the proliferation of lymphoblastoid cell lines with a high ratio of deoxycytidine kinase to deoxynucleotidase. The drug had virtually no effect on the growth of cell lines derived from solid tissues. The CdA inhibited the spontaneous uptake of tritiated thymidine by many T and non-T, non-B acute lymphoblastic leukemia cell specimens at concentrations less than or equal to 5 nM. The same concentrations did not impair either thymidine uptake or granulocyte-monocyte colony formation by normal bone marrow cells. In common with deoxyadenosine, but unlike several other agents affecting purine and purine metabolism, CdA was lethal to resting normal T lymphocytes and to slowly dividing malignant T cells. In both resting and proliferating lymphocytes, the CdA was phosphorylated by deoxycytidine kinase and entered a rapidly turning over nucleotide pool. Dividing lymphocytes also incorporated abundant CdA into DNA. The selective toxicity of CdA toward both dividing and resting lymphocytes may render the drug useful as an immunosuppressive or antileukemic agent.

Inhibitory effects of the nucleoside analogue gemcitabine on prostatic carcinoma cells

“…In agreement with this observation, Braakhuis et al reported the ability of dFdC to affect slowly growing human xenografts 151. An inhibitory effect on nonproliferating cells was also reported for 2-chlorodeoxyandenosine (CdA), another nucleoside analogue used in antineoplastic therapy [30].…”

2‐Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia

“…2-CdA is a purine nucleoside analogue that is cytotoxic to both resting and dividing lymphocytes (Carson et al, 1983). Because of its resistance to adenosine deaminase, 2-CdA promotes the detrimental accumulation of the phosphorylated drug, which is enhanced by high intracellular levels of deoxycytidine kinase (phosphorylation) and low levels of 5 0nucleotidase (dephosphorylation).…”

“…Because of its resistance to adenosine deaminase, 2-CdA promotes the detrimental accumulation of the phosphorylated drug, which is enhanced by high intracellular levels of deoxycytidine kinase (phosphorylation) and low levels of 5 0nucleotidase (dephosphorylation). Accordingly, various lymphocyte subpopulations may be affected differently depending on the enzymatic profile of a particular cell type (Carson et al, 1983). The lymphocytotoxic effects of 2-CdA have been exploited to treat disorders characterized by either clonal lymphoproliferation (hairy cell leukaemia, chronic lymphocytic leukaemia, prolymphocytic leukaemia, Waldenström's macroglobulinaemia, low-grade non-Hodgkin's lymphoma) (Tallman & Hakimian, 1995) or nonclonal autoimmunity (multiple sclerosis) (Beutler et al, 1994).…”

Current and future disease-modifying therapies in multiple sclerosis

“…Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analogue with lymphotoxic effects. It is resistant to adenosine deaminase, mimicking the immune-deficient state of hereditary adenosine deaminase deficiency (92). It causes an accumulation of deoxyneuclotides in selected T-lymphocytes, which is detrimental to the cell's function and proliferation, resulting in their sustained depletion (92).…”